The Master of Puppets: Pleiotropy of PDGFRB and its Relationship to Multiple Diseases

Moura, Denis A. P.; Oliveira, João Ricardo Mendes de

doi:10.1007/s12031-020-01618-4

Cited by 2 publications

(4 citation statements)

References 23 publications

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“…We detected the PDGFRB p.(Glu578Gln) variant in the same imatinib-resistant subline. This tyrosine kinase is a known target of imatinib and is implicated in multiple diseases, e.g., dermatofibrosarcoma protuberans or myofibromatosis ( 45 ). Several variants, but also genetic rearrangements, in PDGFRB were shown to be associated with TKI resistance ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Clonal evolution in tyrosine kinase inhibitor-resistance: lessons from in vitro-models

Kaehler,

Osteresch,

Künstner

et al. 2023

Front. Oncol.

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IntroductionResistance in anti-cancer treatment is a result of clonal evolution and clonal selection. In chronic myeloid leukemia (CML), the hematopoietic neoplasm is predominantly caused by the formation of the BCR::ABL1 kinase. Evidently, treatment with tyrosine kinase inhibitors (TKIs) is tremendously successful. It has become the role model of targeted therapy. However, therapy resistance to TKIs leads to loss of molecular remission in about 25% of CML patients being partially due to BCR::ABL1 kinase mutations, while for the remaining cases, various other mechanisms are discussed.MethodsHere, we established an in vitro-TKI resistance model against the TKIs imatinib and nilotinib and performed exome sequencing.ResultsIn this model, acquired sequence variants in NRAS, KRAS, PTPN11, and PDGFRB were identified in TKI resistance. The well-known pathogenic NRAS p.(Gln61Lys) variant provided a strong benefit for CML cells under TKI exposure visible by increased cell number (6.2-fold, p < 0.001) and decreased apoptosis (-25%, p < 0.001), proving the functionality of our approach. The transfection of PTPN11 p.(Tyr279Cys) led to increased cell number (1.7-fold, p = 0.03) and proliferation (2.0-fold, p < 0.001) under imatinib treatment.DiscussionOur data demonstrate that our in vitro-model can be used to study the effect of specific variants on TKI resistance and to identify new driver mutations and genes playing a role in TKI resistance. The established pipeline can be used to study candidates acquired in TKI-resistant patients, thereby providing new options for the development of new therapy strategies to overcome resistance.

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Section: Discussionmentioning

confidence: 99%

Clonal evolution in tyrosine kinase inhibitor-resistance: lessons from in vitro-models

Kaehler,

Osteresch,

Künstner

et al. 2023

Front. Oncol.

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“…We report here the clinical, neuroimaging and neuropsychological features of 51-year-old Filipina woman with PFBC who was found to harbor a missense variant in the PDGFRB gene. Using next generation genetic sequencing, we detected a c.2756G>A, p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein ( 19 ). Using available computational models, the variant is predicted to be “probably damaging” (PolyPen: 0.981), “deleterious” (SIFT: 0.03), “likely deleterious” (CADD: 32), and “damaging” (MetaLR: 0.56).…”

Section: Discussionmentioning

confidence: 99%

“…PDGFRB gene is known for its pleiotropism, making it central to different molecular systems and implicated in a diverse array of neurological syndromes including infantile myofibromatosis, Kosaki/overgrowth syndrome, Penttitnen syndrome, Sporadic Port-Wine Stain, Moyamoya syndrome, Cornelia de Lange syndrome and PFBC ( 19 ). The PDGFRB protein is a widely expressed pericyte marker ( 22 ), integral in maintaining the blood–brain barrier (BBB).…”

Section: Discussionmentioning

confidence: 99%

“…We describe a case of a 51-year-old woman with cognitive, behavioral, and radiographic features of Fahr’s disease who harbored a variant (Rs14571770) ( 18 ) of the PDGFRB gene (Platelet Derived Growth Factor Receptor beta). The transition c.2756G>A resulted in a glutamine substitution of arginine (p.Arg919Gln) in exon 20, within the tyrosine kinase domain of the PDGFRB protein ( Figure 1 ) ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

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A case report of a patient with primary familial brain calcification with a PDGFRB genetic variant

Al Ali,

Yang,

Phillips

et al. 2023

Front. Neurol.

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Fahr’s disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr’s disease include PDGFB, PDGFRB, SLC20A2, XPR1, MYORG, and JAM2. We present the case of a 51-year-old woman who developed subacute cognitive and behavioral changes primarily affecting frontal-subcortical pathways and parkinsonism in association with extensive bilateral calcifications within the basal ganglia, subcortical white matter, and cerebellum on neuroimaging. Relevant family history included a paternal aunt with parkinsonism at age 50. Normal parathyroid hormone and calcium levels in the patient’s serum ruled out hypoparathyroidism or pseudohypoparathyroidism as causes for the intracranial calcifications. Genetic panel sequencing revealed a variant of unknown significance in the PDGFRB gene resulting in a p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein. To our knowledge this is the first report of a p.Arg919Gln variant in the PDGFRB gene associated with PFBC. Although co-segregation studies were not possible in this family, the location of the variant is within the tyrosine kinase domain of PDGFRB and pathogenicity calculators predict it is likely to be pathogenic. This report adds to the list of genetic variants that warrant functional analysis and could underlie the development of PFBC, which may help to further our understanding of its pathogenesis and the development of targeted therapies for this disorder.

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The Master of Puppets: Pleiotropy of PDGFRB and its Relationship to Multiple Diseases

Cited by 2 publications

References 23 publications

Clonal evolution in tyrosine kinase inhibitor-resistance: lessons from in vitro-models

Clonal evolution in tyrosine kinase inhibitor-resistance: lessons from in vitro-models

A case report of a patient with primary familial brain calcification with a PDGFRB genetic variant

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